HCV represents a major global public health problem, infecting approximately 70 million people worldwide. There is currently no approved vaccine to counter HCV infection, and it is estimated that there are more than 40,000 new infections annually in the US alone with an additional 3-4 million new infections per year in the rest of world (Center for Disease Control). Chronic HCV infection with many of the common viral genotypes is curable by an effective, albeit expensive, antiviral therapy ($70,000/treated patient). Drug treatment is not, however, a feasible route to worldwide eradication of HCV infection, as the cost of doing so would prohibitive. Moreover, successful treatment of a patient infected with one viral genotype does not preclude re-infection with another. The drug treatment approach is also complicated by the fact that most affected individuals are unaware that they are infected, and many engage in risky behaviors, such as intravenous drug use. Simply put, the best long term solution is to invest considerable intellectual and financial resources in discovery and development of a polyvalent vaccine effective against most, if not all, HCV viral genotypes. HCV is an enveloped virus with two surface glycoproteins, E1 and E2, which are critical for entry and immune escape. Since becoming an independent researcher, my laboratory has developed a cost-, labor- and time-efficient method for large-scale production of recombinant glycoproteins in mammalian cell lines with native, post-translational modifications, enabling determination of the core domain of HCV E2 structure in complex with an Fab fragment. This structure revealed that HCV E2 does not share any similarity to other viral glycoproteins, including those from closely related viruses, suggesting that HCV uses a novel entry mechanism.